title: Roundup disrupts male reproductive functions by triggering calcium-mediated cell death in rat testis and Sertoli cells.
abstract: Glyphosate is the primary active constituent of the commercial pesticide Roundup. The present results show that acute Roundup exposure at low doses (36 ppm, 0.036 g/L) for 30 min induces oxidative stress and activates multiple stress-response pathways leading to Sertoli cell death in prepubertal rat testis. The pesticide increased intracellular Ca(2+) concentration by opening L-type voltage-dependent Ca(2+) channels as well as endoplasmic reticulum IP3 and ryanodine receptors, leading to Ca(2+) overload within the cells, which set off oxidative stress and necrotic cell death. Similarly, 30 min incubation of testis with glyphosate alone (36 ppm) also increased (45)Ca(2+) uptake. These events were prevented by the antioxidants Trolox and ascorbic acid. Activated protein kinase C, phosphatidylinositol 3-kinase, and the mitogen-activated protein kinases such as ERK1/2 and p38MAPK play a role in eliciting Ca(2+) influx and cell death. Roundup decreased the levels of reduced glutathione (GSH) and increased the amounts of thiobarbituric acid-reactive species (TBARS) and protein carbonyls. Also, exposure to glyphosate-Roundup stimulated the activity of glutathione peroxidase, glutathione reductase, glutathione S-transferase, γ-glutamyltransferase, catalase, superoxide dismutase, and glucose-6-phosphate dehydrogenase, supporting downregulated GSH levels. Glyphosate has been described as an endocrine disruptor affecting the male reproductive system; however, the molecular basis of its toxicity remains to be clarified. We propose that Roundup toxicity, implicated in Ca(2+) overload, cell signaling misregulation, stress response of the endoplasmic reticulum, and/or depleted antioxidant defenses, could contribute to Sertoli cell disruption in spermatogenesis that could have an impact on male fertility.
authors.affiliation: Departamento de Bioquímica and Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, Santa Catarina, Brazil.
authors.forename: Vera Lúcia
authors.initials: VL
authors.lastname: de Liz Oliveira Cavalli
authors.affiliation: Departamento de Bioquímica and Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, Santa Catarina, Brazil.
authors.forename: Daiane
authors.initials: D
authors.lastname: Cattani
authors.affiliation: Departamento de Bioquímica and Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, Santa Catarina, Brazil.
authors.forename: Carla Elise
authors.initials: CE
authors.lastname: Heinz Rieg
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Paula
authors.initials: P
authors.lastname: Pierozan
authors.affiliation: Departamento de Bioquímica and Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, Santa Catarina, Brazil.
authors.forename: Leila
authors.initials: L
authors.lastname: Zanatta
authors.affiliation: Departamento de Ecologia e Zoologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, Santa Catarina, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Benedetti Parisotto
authors.affiliation: Departamento de Ecologia e Zoologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, Santa Catarina, Brazil.
authors.forename: Danilo
authors.initials: D
authors.lastname: Wilhelm Filho
authors.affiliation: Departamento de Bioquímica and Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, Santa Catarina, Brazil.
authors.forename: Fátima Regina
authors.initials: FR
authors.lastname: Mena Barreto Silva
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Regina
authors.initials: R
authors.lastname: Pessoa-Pureur
authors.affiliation: Departamento de Bioquímica and Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, Santa Catarina, Brazil. Electronic address: ariane.zamoner@ufsc.br.
authors.forename: Ariane
authors.initials: A
authors.lastname: Zamoner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000633:toxicity; D006540:Herbicides / Q000633:toxicity*; D008297:Male; D009336:Necrosis / Q000139:chemically induced; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012708:Sertoli Cells / Q000187:drug effects* / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000473:pathology; D000097797:Glyphosate
chemical_list: D002118:Calcium; D005998:Glycine; D006540:Herbicides; D000097797:Glyphosate
keywords: Calcium homeostasis; Cell death; Cell signaling; Free radicals; Glyphosate; Oxidative stress; Roundup; Sertoli cell